The epigenetic modification of histone H3 lysine 27 trimethylation (H3K27me3) by the embryonic ectoderm development (EED) protein is closely associated with the regulation of transcriptional programs and is implicated in autoimmune diseases. However, the efficacy of targeting H3K27me3 for the treatment of neuroinflammation remains unclear. In this study, we demonstrate that systemic administration of an EED inhibitor diminishes the inflammatory response mediated by dendritic cells (DCs), thereby alleviating experimental autoimmune encephalitis (EAE), a representative mouse model of autoimmune diseases in the central nervous system (CNS). Our findings indicate that EED inhibitors suppress DC migration by upregulating genes in the WNT signaling pathway that are epigenetically marked by H3K27me3. Conversely, inhibiting the WNT pathway partially reverses the impaired DC migration caused by EED inhibitors. Additionally, the genetic deletion of Eed inhibits DC migration and effectively mitigates autoimmune symptoms and inflammatory infiltration into the CNS in EAE. These results highlight EED as a critical regulator of DC migration and suggest its potential as a therapeutic target for autoimmune disorders.
Multiple sclerosis (MS) is an autoimmune neurodegenerative disorder of the central nervous system (CNS) with a significant unmet need for new therapeutic options. Targeting embryonic ectoderm development (EED) is a potential novel therapeutic strategy for treating MS. Herein, based on optimization of potency and pharmacokinetic properties, we report a new class of trisubstituted pyridine derivatives as EED–H3K27me3 inhibitors for MS treatment. Notably, compounds 19 and 21 demonstrate potent EED binding affinity, significantly reduce H3K27me3 levels in dendritic cells (DCs), and effectively inhibit DC migration. Both compounds demonstrate appropriate pharmacokinetic (PK) properties, lymphoid tissue-targeting ability, and favorable in vivo safety profiles. Oral administrations of compounds 19 and 21 dose-dependently reduce spinal cord inflammation and alleviate disease progression in experimental autoimmune encephalomyelitis (EAE) mice. These results establish 19 and 21 as promising lead compounds for the development of EED inhibitors for MS therapy.
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